Environmental exposures that alter asthma risk (C-section, breast feeding) also influence microbial colonization. Dysbiosis regulates mucosal IL-17A and IL-22 levels differently, reducing IL-22 production while enhancing the recruitment of IL-17A-producing cells. As IL-22 mediates homeostasis at mucosal surfaces, and IL-17A production is associated more severe asthma phenotypes, this suggests dysbiosis-induced regulation of asthma pathogenesis may involve an underappreciated dysregulation of the IL-22/IL-17A balance. Our preliminary data show that: (1) perinatal dysbiosis induces lung structural changes, increased baseline airway hyperreactivity (AHR), and exaggerated house dust mite (HDM)-induced asthma phenotype (more severe AHR, elevated chemokine production, enhanced recruitment of IL-17A-producing cells); (2) organoids derived from dysbiosis- exposed epithelial cells demonstrate reduced colony forming efficiency and increased HDM-stimulated chemokine production; (3) IL-17A blockade abrogates perinatal dysbiosis-augmented, HDM-induced AHR; (4) perinatal IL-22 blockade recapitulates some features of perinatal dysbiosis (increased airway responses and lung permeability in HDM-nave adolescent mice); (5) IL-22Ra1 expression is regulated developmentally on pulmonary mesenchymal cells; and (6) supplementation with acetate reverses perinatal dysbiosis-induced alveolar permeability. Thus, we hypothesize that perinatal dysbiosis-induced reduction in neonatal mesenchymal IL-22 signaling drives altered lung development, increased allergen-driven recruitment of IL-17A-producing cells and more severe asthma later in life, and that bacterial metabolite supplementation will reverse these phenotypes. This hypothesis will be tested in three Aims: Aim 1: To define mechanisms driving increased allergen-induced IL-17A-producing cell recruitment and identify the IL-17A-secreting cells driving severe asthma after perinatal dysbiosis, we will determine if perinatal dysbiosis influences immune cell responsiveness to chemotactic signaling, identify pulmonary structural cells responsible for increased chemokine production, and identify which IL-17A-producing ILCs are necessary and sufficient to drive the structural and asthma phenotypes observed after perinatal dysbiosis. Aim 2: To determine if perinatal IL-22 signaling in mesenchymal cells influences pulmonary development, baseline AHR, and the severity of allergen- driven AHR, we will target IL-22-activated signaling pathways in mesenchymal cells during critical neonatal windows in control mice, and supplement animals exposed to perinatal dysbiosis with rIL-22 or IL-22 producing cells, and assess the impact on dysbiosis-induced phenotypes, Aim 3: To determine if dysbiosis-induced alterations in lung development or asthma severity can be reversed by supplementation with bacterial metabolites, we will test the capacity of bacterial metabolites administered prophylactically and therapeutically to reverse dysbiosis-induced phenotypes. Collectively, these studies will elucidate the mechanisms by which perinatal dysbiosis influences asthma development.